Christina Muratore
“Christina Muratore receives the 2009 John and Evelyn Neumeyer’s Research Achievement Award”
Christina is a doctoral student working under Professor Richard Deth on a thesis project entitled “Alternative Splicing of Methionine Synthase as a Biomarker for Oxidative Stress in Aging and Neurological Disorders”.
Methionine synthase (MS), a folate and cobalamin-dependent enzyme involved in the methionine cycle, is composed of five domains, four of which are involved in binding homocysteine (HCY), methylfolate, cobalamin, and SAM. A fifth domain, termed Cap, functions as a linker domain and is able to shield the cobalamin from oxidation by limiting access of reactive oxygen species (ROS) and electrophiles from the surrounding redox environment. Since MS is not active if cobalamin is oxidized, the Cap domain can be considered protective and thus sustains enzyme activity in a threatening redox environment. However, alternative splicing of the Cap domain renders the enzyme inactive and allows HCY to enter the transsulfuration pathway in order to elevate glutathione (GSH) levels and ameliorate oxidative stress. Elevated levels of oxidative stress, which increase with age, are a hallmark feature of many neurological disorders such as Alzheimer's disease and autism. Analysis of MS mRNA in post-mortem samples of human cortex showed a remarkable decline of approximately 100-fold across the lifespan, in both the Cap and cobalamin-binding domains, with the decline of Cap mRNA being greater than the decline of cobalamin-binding domain mRNA in samples over 60 years old. This alternative splicing event may represent a normal adaptive response to aging in order to offset increasing oxidative stress. In addition, MS mRNA levels (both cobalamin-binding and cap domains) were significantly lower in autistic subjects vs. age and sex-matched controls, highlighting a possible adaptive response to neuroinflammation. Through its influence on DNA and histone methylation, decreased MS activity may play a significant role in the causation of autism as well as in the natural process of aging, since epigenetic mechanisms are critical for normal development.